1 the jnc 7 recommendations for initial or combination drug therapy are based on sound scientific...

1

The JNC 7 recommendations for

initial or combination drug therapy

are based on sound scientific evidence.

2

7th Joint National Committee Report on

Prevention, Detection, Evaluation, and

Treatment of High Blood Pressure

3

Algorithm for Drug Treatment of Hypertension

Initial Drug Choices

Without Specific or Compelling Indications

Stage 1 Hypertension

(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, or combination.

Stage 2 Hypertension*

(SBP >160 or DBP >100 mmHg)

2-drug combination for most

(usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

*Combination therapy may also be appropriate initial therapy in patients with diabetes or renal disease

4

Most of the trials upon which the JNC 7

recommendations were based were

multiple drug trials. Specific

recommendations for monotherapy for

specific patient groups may be difficult

to justify.

5

What were the results of the diuretic/

B-blocker controlled long-term

hypertension treatment trials?

6

Results of Therapy

Effect of Antihypertensive DrugTreatment on Cardiovascular Events

*Combined results from 17 randomized placebo controlled treatment trials (48.000 subjects) Diuretic or Beta-blocker based

**All differences are statistically significant J Am Coll Cardiol. 1996;27:1214-1218; Arch Intern Med 1993;S76-S71

% R

edu

cti

on

in

Ev

en

ts *

*

CHF Strokes LVH CVD CHD eventsFatal/Non-fatal Deaths Fatal/Non-fatal

7

A diuretic or diuretic-based treatmentregimen has

• lowered blood pressure

• reduced cerebro and cardiovascular events

• been as well tolerated as any treatment program based on other antihypertensive regimens

8

Specific or Compelling Indications for Different

Medications

Initial TherapyIndication

Thiazide diuretic, ACEI

ACEI, ARB

Thiazide diuretic, BB, ACEI, ARB, CCB

Recurrent stroke prevention

Chronic kidney disease

Diabetes

9

Specific or Compelling Indications for Different

Medications

Initial TherapyIndication

Thiazide diuretic, BB, ACEI, CCB

BB, ACEI, aldosterone antagonist

Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist

High CAD risk

Post-myocardialinfarction

Heart failure

10

JNC 7 Key Messages

Thiazide-type diuretics should be initial drug therapy for most hypertensive patients, alone or combined with other medications

If BP is >160/100 mmHg, therapy should probably started with two medications, one of which should be a thiazide-type diuretic

11

AntihypertensiveTrial Design

• Randomized, double-blind, multi-center clinical trial

• Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic

• 42,418 high-risk hypertensive patients

ALLHAT

12

Step 1Treatment Protocol

8421Doxazosin

* mg/day

40201010Lisinopril

1052.52.5Amlodipine

2512.512.512.5Chlorthalidone

Dose 3*Dose 2*Dose 1*Initial Dose*Step 1 Agent

ALLHAT

13

Percent of Patients Who Received a Step -2 or Step-3 Medication in the ALLHAT

Study

0

20

40

60

80

100

Chlor Aml Lis

1 Year

3 Years

5 Years

Per

cent

*JAMA 2000;283(15):1967-1973

14

ALLHAT Trial

Results indicate that in hypertensive patients (mean age of 67 years) >90% can be controlled with a DBP <90 mm Hg; >60% with a SBP <140

mm Hg and >60% with BPs <140/90 mm Hg – with a less than ideal regimen.

15

Blood Pressure Differences in the

ALLHAT Trial: Diuretic compared to

ACE-I

SBP 4 mm Hg less in Blacks

3 mm Hg less in >65

16

Years to CHD Event0 1 2 3 4 5 6 7

Cu

mul

ativ

e C

HD

Eve

nt R

ate

0

.04

.08

.12

.16

.2

Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

0.810.99 (0.91-1.08)L/C

0.650.98 (0.90-1.07)A/C

p valueRR (95% CI)

ChlorthalidoneAmlodipineLisinopril

17

Cu

mu

lati

ve C

HF

Rat

e

Years to HF

0 1 2 3 4 5 6 70

.03

.06

.09

.12

.15

Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group

<.0011.19 (1.07-1.31)L/C

<.0011.38 (1.25-1.52)A/C

p valueHR (95% CI)

ChlorthalidoneAmlodipineLisinopril

18

Significant Differences in Outcomes in the Clinical Trials

Heart Failure: Other Rx Compared to Diuretics/B-Blockers

LA Nifedipine 2x INSIGHT

Amlodipine 1.4x ALLHAT

Verapamil (high risk) 1.3x CONVINCE

19

Antihypertensive monotherapy is effective in

only about 40-60% of hypertensive patients,

irrespective of the category of the agent that is

used. Therefore, there is frequently a need for

the use of two medications with different

mechanisms of action.

Monotherapy

20BP Control Rates with Low-dose

Beta-blocker /Diuretic Combination Compared to Monotherapy with Other Agents

Placebo Bisoprolol/ Amlodipine EnalaprilN=78 HCTZ N=82 N=84

N=77

† P=.0001 vs Placebo ‡ P=.075 vs Amlodipine*P=.0001 vs Enalapril

Cardiovascular Rev Rep. 1996;17:1-9.

Pat

ien

ts w

ith

DB

P <

90

mm

Hg

(%

)

80

70

60

50

40

30

20

10

0

21

ACE Inhibitor/Diuretic Combination Therapy: Racial Differences in Response

m

m H

g

0

-5

-10

-15

-20

-25

Vidt. J Hypertens. 1984;2(suppl 2):81-88

Enalapril HCTZ Enalapril/HCTZ10mg BID 25 mg BID 10/25 mg BID

(n=66) (n=110) (n=97) (n=92) (n=41)(n=49)

BlackNonblack

- 6.8

-14.3 -14.6-11.8

-21 -21.7

22

Percentage Response (SBP <140 mm Hg; DBP <90 mm Hg) on Combination Therapy with 2

Drugs that Either Do or Do Not Include Hydrochlorothiazide*

100

80

60

40

20

0

30/39 29/63 27/39 32/63

Systolic BP Diastolic BP

*Example, captopril + diltiazem, or captopril +diuretic

From Materson, et al. J Human Hypertension 1995;9:791-796

Pe

rce

nt

Re

spo

ns

e With HCTZWithout HCTZ

77

46 51

69

23

Stroke Risk Reduction ACE/diuretic Treated Patients Compared to Patients

on Other Medications

Lancet 2001:358:1033-41 – PROGRESS Study

(Years)

Pro

po

rtio

n w

ith

Ev

en

t 0.20

0.15

0.10

0.05

0.000 1 2 3 4

24

In several trials in high-risk patients

(HOPE, IRMA, IDNT, RENAAL, and LIFE),

the use of an ACE-I (or an ARB) usually with

a diuretic) reduced CV events more than a

regimen that did not include these medications.

25

Conclusions

• Among non diabetics, incidence of fasting

glucose 126 mg/dL at 4 years was 1.8%

higher in chlorthalidone vs amlodipine, and

3.5% higher in chlorthalidone vs lisinopril.

• Overall, metabolic differences did not

translate into more adverse cardiovascular

events, or into higher all-cause mortality,

with chlorthalidone.

ALLHAT

26

• Are JNC goal levels based on good data?

27

Cardiovascular Events in Diabetics in the Hypertension Optimal Treatment Study

0

5

10

15

20

25

<90 mm Hg (n=501 <80 mm Hg (n= 501)

CV Events/1000 Patient-Years

Major CVEvents

MyocardialInfarctions

CV Mortality

CV events were reduced to a greater degree in diabetics who achievedthe lowest levels of diastolic blood pressure Hansson L, et al. Lancet 1998;351:1755-1762

28

Cardiovascular Event Free Survival

Adjusted for age ANBP2

Female

MaleACEI

DIURETIC||

0.00

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Years Since Randomization

0 1 2 3 4 5

29

Oftentimes, all of the is cannot

be dotted or the Ts crossed in

finalizing recommendations.

These are based on judgement

and interpretation of outcome data.

30

31

32 Results of Different Levels of Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes: B-Blocker compared with ACE Inhibitor-Based Treatment Program

• Better control of blood pressure compared with less aggressive treatment in 8.4-year follow-up of 1148 subjects (achieved blood pressure of 144/82 mm Hg compared with 154/87 mm Hg)

• Reduced risk of:– Stroke (44%)– Fatal strokes (58%)– Death related to diabetes (32%)– Heart failure (56%)– Fatal and nonfatal coronary heart disease events (21%)

(trend but not significant)

• No difference in outcome between a captopril-based and an atenolol- based treatment program

UKPDS . BMJ 1998;317:703-713

33

Suggested Approaches for Initiation of Pharmacologic Therapy

*Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

Low Risk

•Male <55 years of age

•Female <65 years of age

•Stage 1 hypertension (140-159/90-99 mm Hg) with no other risk factors*

Lifestyle modifications for 3 to 4 months

If BP >140/90 mm Hg, begin medicaton

34

Suggested Approaches for Initiation of Pharmacologic Therapy

Medium Risk

Stage 1 hypertension with one other risk factor*

Lifestyle modifications for 2 to 3 months

If BP >140/90 mm Hg, begin medication

*Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

35

High Risk

•BP >140/90 mm Hg with evidence of CVdisease and/or diabetes, with/without other risk factors*

•Stage 2 hypertension

•Stage 1 or 2 hypertension with at least three other risk factors*

Lifestyle modifications and medication

Suggested Approaches for Initiation of Pharmacologic Therapy

*Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity

36

2003

The Antihypertensive and Lipid

Lowering Treatment to Prevent Heart

Attack Trial (ALLHAT)

37

Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular

Events in the Systolic Hypertension in the Elderly program

Active Active Therapy Placebo Therapy Placebo

Major CHD events 9.2 16 6.9 7.6Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7

Nonfatal and fatal strokes 9.7 14.4 4.4 7.5

Major cerebrovascular disease events 21.4 31.5 13.3 10.4

Placebo-treated diabetic patients had about 2-3 times the risk of acardiovascular event as placebo-treated nondiabetics

Diabetic Non Diabetic

38

Nonfatal MI + CHD Death 0.97 (0.88 - 1.08)

All-Cause Mortality 0.96 (0.88 - 1.03)

Combined CHD 1.04 (0.96 - 1.12)

Combined CVD 1.05 (0.99 - 1.12)

Stroke 0.93 (0.81 - 1.08)

Heart Failure 1.33 (1.18 - 1.49)

End Stage Renal Disease 1.12 (0.85 - 1.48)

AHT Age 65+Amlodipine/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Favors Amlodipine Favors Chlorthalidone

0.50 1 2

ALLHAT

05/15/03

39

Nonfatal MI + CHD Death 1.01 (0.91 - 1.12)

All-Cause Mortality 1.03 (0.95 - 1.12)

Combined CHD 1.11 (1.03 - 1.20)

Combined CVD 1.13 (1.06 - 1.20)

Stroke 1.13 (0.98 - 1.30)

Heart Failure 1.20 (1.06 - 1.35)

End Stage Renal Disease 1.01 (0.76 - 1.36)

AHT Age 65+Lisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

ALLHAT

05/15/03

40

05/11/03

ALLHAT

Nonfatal MI + CHD Death 1.06 (0.89 - 1.26)

All-Cause Mortality 1.00 (0.89 - 1.13)

Combined Coronary Heart Disease 1.06 (0.92 - 1.23)

Combined Cardiovascular Disease 1.12 (1.01 - 1.24)

Stroke 1.10 (0.88 - 1.37)

Heart Failure 1.20 (1.00 - 1.45)

End Stage Renal Disease 1.39 (0.84 - 2.31)

0.50 1 2

Favors Lisinopril Favors Chlorthalidone

Relative Risk and 95% Confidence Intervals

Lisinopril/Chlorthalidone

AHT Age 75+

41

Nonfatal MI + CHD Death 0.95 (0.79 - 1.13)

All-Cause Mortality 0.91 (0.81 - 1.03)

Combined Coronary Heart Disease 1.02 (0.88 - 1.18)

Combined Cardiovascular Disease 1.03 (0.92 - 1.14)

Stroke 0.86 (0.68 - 1.09)

Heart Failure 1.22 (1.01 - 1.46)

End Stage Renal Disease 0.98 (0.56 - 1.72)

0.50 1 2

05/11/03

ALLHAT

Favors Amlodipine Favors Chlorthalidone

Relative Risk and 95% Confidence Intervals

Amlodipine/ChlorthalidoneAHT Age 75+

42

3-5 Year Studies Directly Comparing a Diuretic-Based

Treatment Regimen to other Therapies

Diuretic vs B-blocker MRC Elderly

Diuretic vs ACE inhibitor ALLHAT Double blind

ANBP-2 Open

STOP-2 Open

CAPPP (B-blocker or diuretic) Open

43

Systolic and Diastolic Blood Pressure after Randomization

N Engl J Med. 2003;348(7):583-592.

Diastolic

6083

6035 5583 5487 4320 1183

Systolic

6083

6035 5585 5487 4323 1183

ACEI

Diuretic

0

75

80

85

90

95

130

140

150

160

170

0 1 2 3 4 5

Second Australian National Blood Pressure Study (ANBP 2)

• To determine in hypertensive patients aged

65-84 years whether there is any difference

in total cardiovascular events (fatal and non-

fatal) over a 5 year treatment period between

treatment with either a diuretic-based

regimen or an ACE inhibitor-based regimen

ANBP2

45

ANBP 2 Conclusion

Initiation of antihypertensive treatment

in older patients with an ACE inhibitor in

males has an advantage over a diuretic.

46

Primary Result

ANBP2

Hazard Ratio (95% CI) p

ACEI better Diuretic better

0.2 1.0 5.0

All CV Events or Any Death 0.89 (0.79,1.00) 0.05

First CV Event or Any Death 0.89 (0.79,1.01) 0.06

Any Death 0.90 (0.75,1.09) 0.27

47

JNC 7 Key Messages

• For persons over age 50, SBP is more important

than DBP as CVD risk factor

• Normotensive individuals at age 55 have a 90%

lifetime risk for developing hypertension

• Those with SBP 120-139 mm Hg or DBP 80-90

mm Hg should be considered prehypertensive;

they may require lifestyle modifications to

prevent CVD

48

“Intensive control of blood pressure reduces

cardiovascular morbidity and mortality in

diabetic patients regardless of whether low-

dose diuretics, B-blockers, angiotensin-

converting enzyme inhibitors, or calcium

antagonists are used as first-line treatment.”

Grossman, Messerli…Arch Intern Med 2000;?60;2447-2452

49

Primary Result - Females

ANBP2All events

Hazard Ratio (95% CI) p

ACEI better Diuretic better

0.2 1.0 5.0

All CV Events or Any Death 1.00 (0.83,1.21) 0.98

First CV Event or Any Death 1.00 (0.83,1.20) 0.98

Any Death 1.01 (0.76,1.35) 0.94

50

Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular

Events in the Systolic Hypertension in the Elderly program

Active Active Therapy Placebo Therapy Placebo

Major CHD events 9.2 16 6.9 7.6Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7

Nonfatal and fatal strokes 9.7 14.4 4.4 7.5

Major cerebrovascular disease events 21.4 31.5 13.3 10.4

Placebo-treated diabetic patients had about 2-3 times the risk of acardiovascular event as placebo-treated nondiabetics

Diabetic Non Diabetic

51

3-5 Year Studies Directly Comparing a Diuretic-Based

Treatment Regimen to other Therapies

Diuretic vs CCB INSIGHT Double-blind

NORDIL (BB or D) Open

SHELL Open

STOP-2 Open

VHAS Open

52

Results of Tight Blood Pressure Control Compared with Less-Tight BP Control in the

UKPDS Study

24

32

44

3734

47

56

0

10

20

30

40

50

60

Risk Reduction (%)

Any diabetesrelated end-point

Diabetesrelateddeath

Stroke Microvascularendpoints

Retinopathyprogression

Deterior-ation ofvision

Heartfailure

BMJ 1998;317:703-713